Method for obtaining an antiepileptic agent

ABSTRACT

A process for obtaining the pharmaceutical active ingredient, levetiracetam, by means of deaminomethylation of a sufficiently pure enantiomer intermediate (S)-(II), or by means of deaminomethylation of an addition salt thereof with an acid, wherein R 1  and R 2  are either the same or different (C 1 -C 6 )-alkyl radicals, or else R 1  and R 2  together with the nitrogen atom to which they are bonded form a radical selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1-[4-(C 1 -C 4 )-alkylpiperazinyl]. The invention also comprises preparing the sufficiently pure enantiomer intermediate (S)-(II) by treating the corresponding chemically new racemic intermediate (II) with an amine resolving agent, followed by selective crystallisation of a diastereoisomeric salt thereof. It is useful for obtaining levetiracetam on an industrial scale and involves neither hydrogenation nor chromatography.

The present invention refers to obtaining the antiepileptic activeingredient known as levetiracetam, of formula (S)-(I), as well asintermediate compounds for said obtainment.

PRIOR STATE OF THE ART

Levetiracetam is the International Non-proprietary Name (INN) of apharmaceutical active ingredient called(αS)-α-ethyl-2-oxo-1-pyrrolidineacetamide and having the formula:

It is the (S)-enantiomer of the racemic product etiracetam of formula(I), known since the 1970s.

Patent application EP 162,036-A1 discloses levetiracetam for the firsttime and it is indicated that it has particular therapeutic propertiesdistinguishing it from the racemic form, given that it is provided withan activity that is ten times higher with regard to protection againsthypoxia (absence of a suitable amount of oxygen in tissues) and fourtimes higher with regard to protection against cerebral ischemia.

Several processes for obtaining levetiracetam have been disclosed in theart. Patent application EP 162,036-A1 discloses obtaining levetiracetamby reacting (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid with an alkylhaloformate and subsequently with ammonia, as summarized in thefollowing scheme:

The same document discloses obtaining levetiracetam by reacting(S)-2-amino-butanamide with an alkyl 4-halobutyrate or with a4-halobutyryl halide, and subsequent cyclization of alkyl(S)-4-[[1-(aminocarbonyl)propyl]amino]butyrate or of(S)-N-[1-(aminocarbonyl)propyl]-4-halobutanamide thus obtained, assummarized in the attached scheme:

The two previous processes have the drawback of operating attemperatures between −10° C. and −60° C. and the drawback of usingintermediates for cyclization that are not readily obtained.

Patent application GB 2,225,322-A1 discloses a process for obtaininglevetiracetam by hydrogenolysis of(S)-α-[2-(methylthio)ethyl]-(2-oxo-1-pyrrolidine)acetamide by means of adesulfurizing reagent such as Raney nickel or NaBH₄.NiCl₂.6H₂O,according to the following scheme:

A drawback of this industrial-scale process is that it requires specialequipment and special precautions for handling the products.

Other processes are known (for example U.S. Pat. Nos. 6,107,492 and6,124,473) in which levetiracetam is obtained by means of opticalresolution of racemic etiracetam of formula (I). In U.S. Pat. No.6,107,492 resolution is performed by means of preparative highperformance liquid chromatography or by means of a continuous simulatedfluid bed chromatographic system with a chiral stationary phase. U.S.Pat. No. 6,124,473 discloses a continuous simulated fluid bedchromatographic system consisting of at least three chiral stationaryphase columns. These industrial-scale resolution processes are affectedby drawbacks related to using chromatography.

Finally, patent applications WO 01/64,637-A1 and WO 02/26,705-A2disclose processes for preparing levetiracetam by asymmetrichydrogenation of intermediates with a double bond, the hydrogenation ofwhich gives the levetiracetam ethyl group, according to the followingscheme:

The industrial-scale difficulties and hazard of hydrogenation can bementioned in relation to these processes.

It is therefore interesting to have alternative processes for preparinglevetiracetam, particularly if they are easy to industrialize and do notinvolve hydrogenation or chromatographic separation.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, a new process forobtaining levetiracetam (S)-(I) is provided, comprising subjecting asufficiently pure enantiomer intermediate (S)-(II) or an addition saltthereof with an acid to a deaminomethylation reaction,

wherein R₁ and R₂ are the same or different (C₁-C₆)-alkyl radicals, orR₁ and R₂ together with the nitrogen atom to which they are bonded forma radical selected from the group consisting of 1-pyrrolidinyl,1-piperidinyl, 1-morpholinyl, 1-piperazinyl and1-[4-(C₁-C₄)-alkylpiperazinyl]. In a preferred embodiment, thesufficiently pure enantiomer intermediates (S)-(II) are those in whichR₁ and R₂ are both ethyl, or R₁ and R₂ together with the nitrogen atomto which they are bonded, form a radical selected from the groupconsisting of 1-pyrrolidinyl and 1-piperidinyl. Even more preferable isthe embodiment in which R₁ and R₂ are both ethyl.

Sufficiently pure enantiomer intermediate (S)-(II) or an addition saltthereof with an acid is understood as that which has enough enantiomericexcess for industrial-scale preparation, which depends on each specificcase as the person skilled in the art will find when the invention isexploited. From a purely theoretical point of view it would even beenough for it to have an enantiomeric excess simply higher than 50%.However, for industrial-scale preparation it must preferably beunderstood that it is sufficiently pure in this sense when it has apurity, that is, an enantiomeric excess (e.e.), exceeding 70%. It isparticularly advantageous for the enantiomeric excess (e.e.) to begreater than or equal to 80% and very preferably greater than or equalto 90%.

In a particular embodiment, deaminomethylation is carried out on thesufficiently pure enantiomer intermediate (S)-(II), previously obtainedby base treatment of said addition salt with an amine resolving agentacid.

Preferably, deaminomethylation is carried out on an addition salt of thesufficiently pure enantiomer intermediate (S)-(II) with an amineresolving agent acid. Amine resolving agent acid is understood as anyoptically active acid of those commonly used for resolving amines bydiastereoisomeric salt crystallisation, (cfr. J. Jacques et al.,“Enantiomers, Racemates, and Resolutions”, Wiley, 1981; A. N. Collins etal., “Chirality in Industry”, John Wiley & Sons, 1992). In the presentinvention, the preferred acids are those selected from one of theenantiomers of tartaric acid, 1-camphor-10-sulfonic acid, malic acid,dibenzoyltartaric acid, mandelic acid, α-methoxyphenylacetic acid,α-methoxy-α-trifluoromethylphenylacetic acid, pyroglutamic acid,ditoluyltartaric acid or 3-bromocamphor-10-sulfonic acid. Even morepreferably deaminomethylation is carried out on an addition salt of thesufficiently pure enantiomer intermediate (S)-(II) with L-(+)-tartaricacid.

Deaminomethylation can be carried out by treatment with an acid. Theacid is preferably an acid from the group consisting ofp-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid andhydrochloric acid; hydrochloric acid being especially preferable.Alternatively, the reaction can be carried out by treatment with a base,where this base is preferably ammonia, pyrrolidine, piperidine,1,2-trans-diaminocyclohexane, diisopropylamine, butylamine, potassiumhydroxide and sodium hydroxide; butylamine being particularlypreferable. It can also be carried out with the same bases in thepresence of a minor amount of its hydrochloride. The reaction ispreferably carried out in water or in an organic solvent/water mixture,being able to use as organic solvents, for example, (C₁-C₅) aliphaticmonoalcohols, (C₆-C₈) hydrocarbons, (C₃-C₉) aliphatic esters, (C₁-C₃)aliphatic chlorides and mixtures of any of them, at a temperaturecomprised between 0° C. and the reflux temperature of the solvent systemused.

Another aspect of the invention refers to a process for obtaining thesufficiently pure enantiomer intermediate (S)-(II) addition salt with anamine resolving agent acid that can generally be prepared by treatingthe corresponding racemic intermediate (II) with one of these acids,followed by one or several selective crystallisations of thisdiastereoisomeric salt in a suitable solvent system, where said salt isinsoluble at a cold temperature, cold temperature being understood asnot only room temperature but also temperatures below room temperaturewhich can readily be reached on an industrial scale.

(C₁-C₅) aliphatic monoalcohols, mixtures of (C₁-C₅) aliphaticmonoalcohols with (C₆-C₈) aliphatic or aromatic hydrocarbons andmixtures of (C₁-C₅) aliphatic monoalcohols with (C₃-C₇) aliphaticketones can be used as a solvent system. In a preferred embodiment, thesolvent system is selected from the group consisting of methanol,ethanol, methanol/heptane mixtures, methanol/methyl isobutyl ketonemixtures, methanol/methyl ethyl ketone mixtures, ethanol/methyl isobutylketone mixtures, ethanol/methyl ethyl ketone mixtures andmethanol/acetone mixtures. This reaction for obtaining the salt iscarried out by means of well-known techniques, comprising reacting theracemic intermediate (II) with the amine resolving agent acid and, whenrequired, seeding with a sample of the addition salt to be obtained,finally separating the crystallised product by means of filtering. Thesuitable conditions will be chosen by the person skilled in the art ineach case according to parameters such as product concentration, type ofsolvent and the like, parameters that can be readily determined by meansof routine tests.

The racemic intermediate (II) is obtained by reacting etiracetam (I)with formaldehyde, both free formaldehyde and in paraformaldehyde form,and a free amine of formula HNR₁R₂ or as a hydrochloride, wherein R₁ andR₂ have the previously defined meaning, according to the followingscheme:

The etiracetam used as a starting material can be obtained by theprocess disclosed in British patent GB No 1,309,692.

A third aspect of the present invention refers to the new intermediatecompounds of formula (II), their stereoisomers, mixtures thereof,solvates and addition salts of any of the foregoing, as well as solvatesof said addition salts and hydrates of said addition salts, wherein R₁and R₂ are either the same or different (C₁-C₆-alkyl radicals, or elseR₁ and R₂, together with the nitrogen atom to which they are bonded,form a radical selected from the group consisting of 1-pyrrolidinyl,1-piperidinyl, 1-morpholinyl, 1-piperazinyl and1-[4-(C₁-C₄)-alkylpiperazinyl]. The most preferred among them are thosein which R₁ and R₂ are either both ethyl, or else R₁ and R₂ togetherwith the nitrogen atom to which they are bonded, form a radical selectedfrom the group consisting of 1-pyrrolidinyl and 1-piperidinyl. Theintermediate compound (II) in which R₁ and R₂ are both ethyl isparticularly preferred.

Preferable among the addition salts of intermediate (II), or itsstereoisomers, or of the mixtures thereof, are the previously mentionedsalts with amine resolving agent acids. Particularly preferable amongthem are those salts in which the amine resolving agent acid isL-(+)-tartaric acid, such as(S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideL-(+)-tartrate,(S)-N-[(1-pyrrolidinyl)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideL-(+)-tartrate or(S)-N-[(1-piperidinyl)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideL-(+)-tartrate, as well as hydrates and solvates of all the previoussalts.

In comparison with processes for preparing levetiracetam known in theart, the process of the present invention provides a simple and readilyindustrialised alternative for obtaining enantiomerically purelevetiracetam from a new sufficiently pure enantiomer intermediate(S)-(II) or from the addition salts thereof with amine resolving agentacids. Intermediate (S)-(II) is in turn readily obtained from racemicetiracetam with a good yield and by means of relatively economicalconversions. The solvents used are common, inexpensive and little toxic,and L-(+)-tartaric acid is a natural, inexpensive and non-toxic acid.Furthermore, the opposite (R)-enantiomer absolute configuration ofintermediate (S)-(II) or its addition salts with amine resolving acids,unsuitable for preparing levetiracetam, is easy to racemize in a mannerequal to that shown in example 11 for the (S)-enantiomer. This allowsrecycling in the levetiracetam production process, preventing the lossof starting material.

The invention is illustrated below by means of several detailedexamples, which must not be considered to be limitative of the scope ofprotection. Based on the information provided and general commonknowledge, how to carry out the invention in its entire scope will beevident for the person skilled in the art. The word “comprise” andvariants thereof are used in this description and claims in the sensethat does not mean to exclude other elements, components or steps.

EXAMPLES Example 1 Preparation ofN-[(1-piperidinyl)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide

58.6 ml of a 35% w/w solution of formaldehyde in H₂O with 10% methanolwere added to a dispersion of 50 g of etiracetam in 250 ml of ethanol in15 minutes and at room temperature. 58 ml of piperidine were added tothe resulting solution in 45 minutes and was maintained at 50° C. for 24hours. The solvent was evaporated under reduced pressure, and afteradding 233 ml of xylene, the solvent was evaporated again, an operationthat was repeated another time, obtaining 89.8 g of a semi-solid, thecrystallisation of which from 54 ml of heptane allowed obtaining 65.5 gof the compound indicated in the example title, characterised by thefollowing analytical data: mp: 92° C.; ¹H-NMR: (400 MHz, CDCl₃, ppm):0.91 (t, 3H), 1.35-1.45 (m, 2H), 1.5-1.6 (m, 4H), 1.65-1.75 (m, 1H),1.90-2.10 (m, 3H), 2.35-2.50 (m, 6H), 3.40-3.50 (m, 2H), 4.05-4.15 (m,2H), 4.40-4.50 (m, 1H), 6.8 (bs, 1 H); ¹³C-NMR (400 MHz, CDCl₃, ppm):10.4 (CH₃), 18.1 (CH₂), 21.1 (CH₂), 23.9 (CH₂), 25.7 (2×CH₂), 31.0(CH₂), 43.8 (CH₂), 50.9 (2×CH₂), 56.6 (CH); 61.6 (CH₂), 170.5 (C), 175.8(C); IR (film, KBr, cm⁻¹): 3309, 2935, 1668, 1539, 1435, 1287, 1113,861.

Example 2 Preparation ofN-[(1-pyrrolidinyl)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide

58.6 ml of a 35% w/w solution of formaldehyde in H₂O with 10% methanolwere added to a dispersion of 50 g of etiracetam in 250 ml of ethanol at15° C. and in 20 minutes. Then 48.7 ml of pyrrolidine were added in 50minutes. This was heated at 50° C. and maintained for 24 hours. Then thesolvent was evaporated under reduced pressure, and after adding 233 mlof xylene, the solvent was evaporated again, an operation that wasrepeated another time, obtaining 81.6 g of the compound indicated in theexample title in oil form, the recrystallisation of which from 49 ml ofxylene allowed obtaining 42.3 g of the compound indicated in the exampletitle, characterised by the following analytical data: mp: 75° C; ¹H-NMR(400 MHz, CDCl₃, ppm): 0.91 (t, 3H), 1.65-1.80 (m, 5H), 1.90-2.10 (m,3H), 2.35-2.50 (m, 2H), 2.55-2.65 (m, 4H), 3.40-3.50 (m, 2H), 4.20 (d,2H), 4.43 (t, 1 H), 6.85 (bs, 1H); ¹³C-NMR (400 MHz, CDCl₃, ppm): 10.5(CH₃), 18.1 (CH₂), 21.1 (CH₂), 23.6 (2×CH₂), 31.0 (CH₂), 43.8 (CH₂),50.1 (2×CH₂), 56.7 (CH), 57.2 (CH₂), 170.4 (C), 175.8 (C); IR (film,KBr, cm⁻¹): 3307, 2966, 1667, 1539, 1288, 1206, 1140.

Example 3 Preparation ofN-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide

2.3 ml of a 35% w/w solution of formaldehyde in H₂O with 10% methanolwere added to a dispersion of 2 g of etiracetam in 4 ml of ethanol at17° C. 2.4 ml of diethylamine were added immediately after that in 15minutes without exceeding 25° C., after which the reaction wasmaintained standing and at room temperature for 4 days. Then the solventwas evaporated under reduced pressure and, after adding 9.6 ml ofheptane, the solvent was evaporated again, an operation that wasrepeated another time, obtaining 3.03 g of the compound indicated in theexample title in oil form, characterised by the following analyticaldata: ¹H-NMR (400 MHz, CDCl₃, ppm): 0.91 (t, 3H), 1.08 (t, 6H),1.65-1.75 (m, 1H), 1.90-2.10 (m, 3H), 2.35-2.50 (m, 6H), 3.40-3.50 (m,2H), 4.24 (dd, 2H), 4.44 (t, 1 H), 6.75 (bs, 1 H); ¹³C-NMR (400 MHz,CDCl₃, ppm): 10.4 (CH₃), 12.8 (2×CH₃), 18.1 (CH₂), 21.1 (CH₂), 31.0(CH₂), 43.8 (CH₂), 45.2 (2×CH₂), 55.9 (CH₂), 56.7 (CH), 170.6 (C), 175.7(C); IR (film, KBr, cm⁻¹): 3316, 2968, 1667, 1539, 1288, 1200, 993.

Example 4 Preparation of(S)-N-[(1-pyrrolidinyl)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideL-(+)-tartrate (1:1)

3.14 g ofN-[(1-pyrrolidinyl)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide weresuspended in 13 ml of methanol. 1.86 g of L-(+)-tartaric acid were addedand it was heated at 60° C. 13 ml of heptane were added to the resultingsolution, after which it was left to cool to 40° C. It was seeded with asample of the compound indicated in the example title to startcrystallisation. Then it was slowly cooled to 0-5° C. and maintained atthis temperature for 4 hours. The crystallised product was separated byfiltration and washed twice over the filter with 1 ml of methanol eachtime, and finally once with 6 ml of hexane. 2.86 g of the compoundindicated in the example title was obtained with a diastereoisomericexcess (d.e.): 69% measured by means of HPLC analysis of the free basewith a chiral column (Chiralcel OD, hexane/isopropanol, 220 nm).

Example 5 Preparation of(S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideL-(+)-tartrate (1:1) in methanol

3.17 g of L-(+)-tartaric acid were added to a suspension of 5.4 g ofN-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide in 7.4ml of methanol, and it was heated under reflux. It was left to cool toroom temperature and seeded with a sample of the compound indicated inthe example title at said temperature to start crystallisation. Then itwas cooled to 0-5° C. and maintained at this temperature for 4 hours.The crystallised product was separated by filtration and washed with 2ml of methanol. 3.16 g of the compound indicated in the example titlewere obtained with: d.e.: 79% measured by means of HPLC analysis of thefree base with a chiral column (Chiralcel OD, hexane/isopropanol, 220nm). Product recrystallisation obtained from 6.7 ml of methanol allowedobtaining 1.29 g of the compound indicated in the example titlecharacterised by the following analytical data: d.e.: >99.5% measured bymeans of HPLC analysis on the free base with a chiral column (ChiralcelOD, hexane/isopropanol, 220 nm); IR (film, KBr, cm⁻¹): 3283, 2971, 1670,1546, 1463, 1351, 1215, 1128, 1075.

Example 6 Preparation of(S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideL-(+)-tartrate (1:1) in a methanol/methyl isobutyl ketone Mixture

2.95 g of L-(+)-tartaric acid were added to a suspension of 5.02 g ofN-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide in 6.4ml of a methanol/methyl isobutyl ketone (4:1) mixture and this washeated at 60° C. It was left to cool at room temperature and was seededwith a sample of the compound indicated in the example title to startcrystallisation. Then it was slowly cooled to 0-5° C. and maintained atthis temperature for 4 hours. The crystallised product was separated byfiltration and washed twice over the filter with 2 ml of methanol eachtime, obtaining 3.18 g of the compound indicated in the example titlecharacterised by the following analytical data: d.e.: 81% measured bymeans of HPLC analysis on the free base with a chiral column (ChiralcelOD, hexane/isopropanol, 220 nm). Product recrystallisation obtained from6.6 ml of methanol allowed obtaining 1.5 g of the compound indicated inthe example title with d.e.: >99.5% determined by means of HPLC analysisof the free base with a chiral column (Chiralcel OD, hexane/isopropanol,220 nm).

Crystallisation was performed in the following solvent systems also withsimilar results: ethanol; methanol/heptane; ethanol/methyl isobutylketone; ethanol/methyl ethyl ketone and methanol/acetone.

Example 7 Preparation of(S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide

1.21 g of(S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideL-(+)-tartrate (1:1) were dissolved in 6 ml of saturated sodiumbicarbonate solution and 10 ml of dichloromethane. The phases wereseparated and the aqueous phase was extracted with dichloromethane (6×10ml). The pooled organic phases were dried over anhydrous sodium sulfateand subsequently concentrated to dryness. 0.6 g of the compoundindicated in the example title was obtained in colorless oil form,characterised by the following analytical data: enantiomeric excess(e.e.) >99.5% determined by means of HPLC analysis with a chiral column(Chiralcel OD, hexane/isopropanol, 220 nm); [α]²³ _(D)=−71.5° (c=1.01 inacetone).

Example 8 Preparation of Levetiracetam by Deaminomethylation of anAmmonium Salt with Butylamine

5.0 g of(S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideL-(+)-tartrate (1:1) were suspended in 21 ml of a MeOH/H₂O (1:1)mixture. 3.6 ml of butylamine were added and the resulting mixture wasmaintained under stirring at room temperature for 7 hours. Then it wasconcentrated to dryness. The resulting crude product (8.6 g) wasdissolved in 34 ml of dichloromethane, 8.6 ml of saturated sodiumchloride solution and 8.6 ml of water. The phases were separated and theaqueous phase was extracted with dichloromethane (6×26 ml). The pooledorganic phases were dried over Na₂SO₄ and finally concentrated todryness. 2.68 g of a crude product were obtained which wasrecrystallised twice from methanol, the first time with 2 ml of methanoland the second time with 1 ml of methanol, obtaining 0.76 g of thecompound indicated in the example title, characterised by the followinganalytical data: chemical purity: >99% area/area and (e.e.) >99.8%, bothdetermined by means of HPLC analysis with a chiral column (Chiralcel OD,hexane/isopropanol, 220 nm); [α]²³ _(D)=−89.8° (c=1.00 in acetone).

Example 9 Preparation of Levetiracetam by Deaminomethylation of anAmmonium Salt in a 1% Methanol/HCl Mixture

5.0 g of(S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideL-(+)-tartrate (1:1) were suspended in 6.2 ml of methanol and 57 ml of a1% hydrochloric acid aqueous solution. The resulting mixture wasmaintained under reflux for 12 hours. Then it was concentrated todryness. The resulting crude product (9.86 g) was dissolved in 25 ml ofdichloromethane and 10 ml of saturated sodium chloride solution. Thephases were separated and the aqueous phase was extracted withdichloromethane (6×15 ml). The pooled organic phases were dried overNa₂SO₄ and finally concentrated to dryness. 1.91 g of a solid wereobtained which, after successively recrystallising it from methanol,gave similar results as in the previous example.

Example 10 Preparation of Levetiracetam by Deaminomethylation of a FreeAmine

0.1 g of(S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideL-(+)-tartrate (1:1) were suspended in 2.5 ml of a MeOH/H₂O (1:4)mixture. Then 116 μL of butylamine were added and the resulting solutionwas maintained under agitation at room temperature for 6 hours. Then thereaction mixture was concentrated to dryness and subsequentlyrecrystallised from methanol, obtaining similar results as those inExample 8.

Example 11 Racemization of(S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide(S)-(II)

0.2 g of(S)-N-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamideand 8.5 mg of sodium methoxide were suspended in 2.5 ml of methanol andwas maintained at 65° C. for 24 hours. The reaction mixture was taken topH 1-3 with 0.1 N hydrochloric acid and then to pH 8-9 with sodiumbicarbonate. Then the aqueous phase was extracted with dichloromethane(3×3 ml). The pooled organic phases were dried over anhydrous sodiumsulfate and finally concentrated to dryness. 68 mg ofN-[(1,1-diethylamino)methyl]-α-ethyl-2-oxo-1-pyrrolidineacetamide (I)were obtained with d.e.: 8% determined by means of HPLC with a chiralcolumn (Chiralcel OD, hexane/isopropanol, 220 nm).

1. A process for preparing levetiracetam (S)-(I), comprising subjectingthe sufficiently pure enantiomer intermediate of general formula(S)-(II) or an addition salt thereof with an acid, to adeaminomethylation relation,

wherein R₁ and R₂ are the same or different (C₁-C₆)-alkyl radicals, orR₁ and R₂ together wit the nitrogen atom to which they are bonded, forma radical selected from the group consisting of 1-pyrrolidinyl,1-piperidinyl, 1-morpholinyl, 1-piperazinyl and1-[4-)C₁-C₄)-alkylpiperazinyl].
 2. A process according to claim 1,wherein R₁ and R₂ are both ethyl, or R₁ and R₂ together with thenitrogen atom to which they are bonded form a radical selected from thegroup consisting of 1-pyrrolidinyl and 1-piperidinyl.
 3. A processaccording to claim 2, wherein R₁ and R₂ are both ethyl
 4. A processaccording to claim 1, wherein deaminomethylation is carried out on thesufficiently pure enantiomer intermediate (S)-(II), previously obtainedby base treatment of an addition salt of said intermediate with an amineresolving agent acid.
 5. A process according to claim 1, whereindeaminomethylation is carried out on an addition salt of compound(S)-(II) with an acid, on a hydrate of said addition salt or on asolvate of said addition salt.
 6. A process according to claim 5,wherein deaminomethylation is carried out on an addition salt ofcompound (S)-(II) with an amine resolving agent acid.
 7. A processaccording to claim 6, wherein the amine resolving agent acid is anenantiomer of an acid selected from the group consisting of tartaricacid, 1-camphor-10-sulfonic acid, malic acid, dibenzoyltartaric acid,mandelic acid, α-methoxyphenylacetic acid,α-methoxy-α-trifluoromethylphenylacetic acid, pyroglutamic acid,ditoluyltartaric acid and 3-bromocamphor-10-sulfonic acid.
 8. A processaccording to claim 7, wherein the amine resolving agent acid isL-(+)-tartaric acid.
 9. A process according to claim 1, whereindeaminomethylation is carried out by treatment with an acid.
 10. Aprocess according to claim 9, characterised in that said acid is an acidfrom the group consisting of p-toluenesulfonic acid, methanesulfonicacid, benzenesulfonic acid and hydrochloric acid.
 11. A processaccording to claim 10, wherein the selected acid is hydrochloric acid.12. A process according to claim 1, wherein deaminomethylation iscarried out by treatment with a base.
 13. A process according to claim12, characterised in that said base is a base from the group consistingof ammonia, pyrrolidine, piperidine, 1,2-trans-diaminocyclohexane,diisopropylamine, butylamine, potassium hydroxide and sodium hydroxide.14. A process according to claim 13, wherein the selected base isbutylamine.
 15. A process according to claim 1, wherein the additionsalt of the sufficiently pure enantiomer intermediate (S)-(II) with anamine resolving agent acid is previously prepared by treating thecorresponding racemic intermediate (II) with said acid, followed by oneor several selective crystallizations of this diastereoisomeric salt ina solvent system in which said salt is insoluble at a cold temperature;and wherein R₁ and R₂ have the previously defined meanings.


16. A process according to claim 15, wherein the solvent system isselected from the group consisting of (C₁-C₅) aliphatic monoalcohols,mixtures of (C₁-C₅) aliphatic monoalcohols with (C₆-C₈) aliphatic oraromatic hydrocarbons and mixtures of (C₁-C₅) aliphatic monoalcoholswith (C₃-C₇) aliphatic ketones.
 17. A process according to claim 16,wherein the solvent system is selected from the group consisting ofmethanol, ethanol, methanol/heptane mixtures, methanol/methyl isobutylketone mixtures, methanol/methyl ethyl ketone mixtures, ethanol/methylisobutyl ketone mixtures, ethanol/methyl ethyl ketone mixtures andmethanol/acetone mixtures.
 18. A process according to claim 1, whereinthe racemic intermediate (II) is obtained by reaction etiracetam (I)with formaldehyde and an amine of formula HNR₁R₂ in an inert solvent;and wherein R₁ and R₂ have the same meaning as in the previous claims.


19. A process according to claim 1, characterized in that saidsufficiently pure enantiomer intermediate of general formula (S)-(II) oran addition salt thereof with an acid, has an enantiomeric excessgreater than or equal to 70%.
 20. A process according to claim 19,characterised in that said sufficiently pure enantiomer intermediate ofgeneral formula (S)-(II) or an addition salt thereof with an acid, hasan enantiomeric excess greater than or equal to 80%.
 21. A processaccording to claim 19, characterised in that said sufficiently pureenantiomer intermediate of general formula (S)-(II) or an addition saltthereof with an acid, has an enantiomeric excess greater than or equalto 90%.
 22. An intermediate compound of formula (II), its stereoisomers,mixtures thereof, solvates, addition salts of any of the foregoing,solvates of said addition salts, and hydrates of said addition salts,wherein R₁ and R₂ are the same or different (C₁-C₆)-alkyl radicals, orR₁ and R₂ together with the nitrogen atom to which they are bonded forma radical selected from the group consisting of 1-pyrrolidinyl,1-piperidinyl, 1-morpholinyl, 1-piperazinyl and1-[4-(C₁-C₄)-alkylpiperazinyl].


23. A compound according to claim 22 wherein, R₁ and R₂ are both ethyl,or R₁ and R₂ together with the nitrogen atom to which they are bondedform a radical selected from the group consisting of 1-pyrrolidinyl and1-piperidinyl.
 24. A compound according to claim 23, wherein R₁ and R₂are both ethyl.
 25. A compound according to claim 22, wherein saidcompound is an addition salt with an amine resolving agent acid. 26.Addition salts according to claim 25, wherein the amine resolving agentacid is an enantiomer of an acid selected from the group consisting oftartaric acid, 1-camphor-10-sulfonic acid, malic acid, dibenzoyltartaricacid, mandelic acid, α-methoxyphenylacetic acid,α-methoxy-α-trifluoromethylphenylacetic acid, pyroglutamic acid,ditoluyltartaric acid and 3-bromocamphor-10-sulfonic acid.
 27. Additionsalts according to claim 26, wherein the amine resolving agent acid isL-(+)-tartaric acid.